Fri. Sep 20th, 2019

Chronic Myelogenous Leukemia maintaining Cancer Stem Cells

Many of the patients with chronic myelogenous leukemia may be helped to cure with tyrosine kinase inhibitors. These result in extended endurance. Howeverinert leukemic stem cells persist in the patients so they must keep up the inhibitor treatment.

These ‘sleeper cell’ stem cells are kept in the bone marrow where the bone marrow niches are understood to preserve usual hematopoietic stem cells.

Ravi Bhatia (M.D., and colleagues at the University of Alabama at Birmingham, University of Zurich and Osaka University), in research, states how the niche-specific expression of a specific chemokine by a certain type of bone marrow cell checks the quiescence of these treatment-resilient leukemic stem cells. The chemokine (CXCL12), and the bone marrow cells that express it are mesenchymal stromal cells, which are known to help support normal stem cells.

“The persistence of dormant, primitive leukemic stem cells in patients receiving tyrosine kinase inhibitor treatment is a major barrier to a cure in chronic myelogenous leukemia,” Bhatia states. “This work identifies the specific mesenchymal stromal cell niche cells that are responsible for maintaining leukemic stem cells in a quiescent and treatment-resistant state, and indicates that targeting these niche interactions can activate leukemia stem cells, make them sensitive to treatment and enhance their elimination.”

Four kinds of cells in bone marrow are recognized to profusely produce CXCL12. Bhatia and his colleagues were successful in producing directed removals of the gene for CXCL12 in every cell type (in mouse experiments).

It was found that deleting CXCL12 in mesenchymal stromal cells, but not when deleting from the other three cell types, heightened leukemia growth and decreased survival in the mice. But the stem cells became sensitive to the tyrosine kinase treatment, consequently increasing their removal.

Imaging of Bone marrow showed that stromal cells figured how to co-localize with the stem cells in isolated sites in the bone marrow. These regions were lost to CXCL12 elimination, supporting the significance of CXCL12 appearance in preserving leukemia stem cell niches.

“These results, therefore, reveal that CXCL12-expressing mesenchymal stromal cells function as specific regulatory niches that maintain quiescent, treatment-resistant leukemic stem cells in the bone marrow,” says Bhatia.

As compared to mesenchymal stromal cells, removal of the CXCL12 expression resulted in a reduction of chronic myelogenous leukemia stem cell figures, and it prolonged the survival rates for the mice, suggesting that CXCL12-expressing endothelial cell niches help in preserving stem cells.